tbuckley/cabot-search huggingface dataset:
Next-generation sequencing (NGS) for identifying actionable molecular alterations in patients with newly diagnosed and recurrent IDHwt-glioblastoma (GBM): A large mono-institutional experience.
Authors: Marta Padovan, Marta Maccari, Alberto Bosio, Salvatore Vizzaccaro, Ilaria Cestonaro, Martina Corrà, Mario Caccese, Giulia Cerretti, Matteo Fassan, Vittorina Zagonel, Giuseppe Lombardi
Journal: Journal of Clinical Oncology (2022)

3139 Background: NGS panels allow the identification of alterations within hundreds of cancer-related genes and can guide a personalized strategy in glioma treatment. Methods: From Nov 2019 to Jan 2022 at Veneto Institute of Oncology, Padua, Italy, a large cohort of IDHwt-GBM tissues was analyzed by NGS (FoundationOneCDx). We identified all potential actionable molecular alterations at diagnosis and/or at recurrence. High tumor mutational burden (TMB) was defined as ≥10 mutations/megabase. Results: We analyzed 429 IDHwt-GBM samples: NGS profile was available for 419 samples (97.7%); sample failures in 10 cases (2.3%). 351 (84%) and 68 (16%) GBM samples derived from surgery at diagnosis and recurrence, respectively. All patients received radiotherapy and/or temozolomide as first line therapy. Among all the analyzed samples, the most frequent actionable molecular alterations were: CDKN2A (57%), CDKN2B (53%), EGFR amplification (39%), EGFR mutation (24%), PTEN loss (27%), RB1 (23%), NF1 (18%), PIK3CA (18%), CDK4 (15%), MDM2 (10%), PDGFRA (8%), BRCA1-2 (7%), FGFR1-3 (7%), Myc (6%), JAK (6%), ROS1 (5%), METmut (2%), METampl (2%), BRAF V600E (2%). No NTRK1/2/3 druggable alterations were observed. High TMB was found in 18 samples. Incidence of actionable molecular alterations in newly diagnosed and relapsed GBM samples is described in the Table. The incidence of alteration of EGFR (ampl/mut), RB1, PIK3CA was statistically different between the two subgroups of samples (Fisher test). To date, 10% of patients received a personalized treatment as compassionate use, off-label use or in clinical trials (9 Dabrafenib/Trametinib, 8 Alpelisib, 3 Erdafitinib, 2 Ipatasertib, 1 Alectinib, 1 Capmatinib, 1 Palbociclib, 1 Entrectinib, 1 Pamiparib). Activity analysis is still ongoing. Conclusions: NGS is feasible in GBM samples. Potentially, a high rate of patients could receive a personalized treatment. The activity analysis is ongoing. However, the incidence of actionable molecular alterations may differ between diagnosis and recurrent GBM samples. [Table: see text]
NURS-04. Marijuana, Hemp, and the Child with Cancer: Education for Nurses
Authors: Molly Hemenway
Journal: Neuro-Oncology (2022)

Abstract Many pediatric oncology patients report medical marijuana (MMJ) and hemp-based cannabidiol (CBD) use. Nearly 4,000 minors are registered users of marijuana in Colorado, the first state in the United States of America (USA) to legalize recreational marijuana. Medical marijuana is legalized in 37 states and four territories in the USA. Additionally, due to the bipartisan Farm Bill passed in December of 2018, hemp is federally legal. Forty-three countries have also legalized medical marijuana. With increased legality and many countries decriminalizing marijuana, the use of MMJ and hemp-based CBD is also increasing. This upsurge in use raises significant concerns with pharmacological interactions with CBD and the medications routinely administered to children with cancer (including chemotherapy). Cannabis-derived pharmaceuticals can also have pharmacological interactions. Nurses are the frontline for discussions with patients about MMJ and must be aware of the emerging field of MMJ in pediatric cancer. Education including the difference between tetrahydrocannabinol (THC) and CBD and their indications, extraction methods and safety, product types, infection control, and dosing considerations are important for nurses to learn. Nurses with increased knowledge will then help patients and families make educated and safer choices in treating their children for tumor treatment and side effect management with MMJ and hemp-based CBD. Additionally, nurses can influence patient care protocols and processes for alternative therapy administration enabling an open dialogue between providers, parents, and patients regarding treatments, symptoms, adverse effects, and drug interactions.
Methylated DNA markers in early detection of lymphoma: Discovery, validation, and clinical pilot.
Authors: Thomas E. Witzig, William R. Taylor, Douglas W. Mahoney, William R. Bamlet, Patrick H. Foote, Kelli Burger, Karen A. Doering, Mary E. Devens, Jacquelyn R. Arndt, Maria O'Connell, Calise K. Berger, Anne Novak, James Robert Cerhan, Jacquelyn Hennek, Viatcheslav E. Katerov, Hatim T. Allawi, Dragan Jevremovic, Linda N Dao, Rondell P. Graham, John B. Kisiel
Journal: Journal of Clinical Oncology (2022)

7562 Background: Lymphoma is the 6th most common cancer and a top 10 cause of cancer deaths. To date, there are no blood test approaches to population screening, and accurate surveillance markers are limited. Methylated DNA markers (MDMs) are broadly informative for early detection of cancer but have not been extensively studied for lymphomas. We sought to discover and validate MDMs in DNA extracted from lymphoma tissue, then test these MDMs in archival blood plasma specimens. Methods: Reduced representation bisulfite sequencing (RRBS) was performed on DNA extracted from a discovery set of frozen tissues of classic Hodgkin lymphoma (CHL, n=24), non-Hodgkin lymphoma (NHL, n=78: T-cell-TCL (8); diffuse large B-cell-DLBCL (18); follicular-FL (12); mantle cell-MCL (20); marginal zone-MZL (15)), and lymphoma cell line samples (27); controls included benign lymph node (n=11) and healthy donor buffy coat (n=30). 30 MDMs were ranked by fold-change and AUC and used to design methylation-specific PCR assays for biological validation on independent DNA samples extracted from FFPE tissue from 13 normal lymph node and 63 lymphoma samples and 36 buffy coats from healthy patients. Target enrichment long-probe quantitative-amplified signal assays were developed for 16 MDMs and then assayed in plasma-extracted, bisulfite-converted DNA samples from 390 independent treatment-naïve lymphoma patients (100 CHL and 290 NHL:100 DLBCL, 73 FL, 41 MCL, 41 MZL, 35 TCL), and 210 controls without cancer. Lymphoma plasma samples and 159 controls were provided by the Lymphoma SPORE (CA97274); 51 controls came from a 7-county population archive. Classification of lymphoma cases vs controls was modeled with random forest method and cross-validated across 500 bootstrap samples of each dataset. Results: For MDMs tested in DNA from independent biological validation samples, cross-validated random forest models identified 60/63 cases (95% sensitivity) and 12/13 normal controls (92% specificity). In plasmas, a panel of 16 MDMs ( ZNF503, VWA5B1, HOXA9_5195, GABRG3, ITGA5, MAX_chr17_793, BNC1_2407, CDK20, MAX_chr4_184, TPBG, DNAH14, SYT2, CACNG8, FAM110B, and NRN1) detected 78% (95% CI, 74-82%) of lymphoma cases at 90% specificity. Excluding MZL and TCL, sensitivity increased to 84% (80-88%) including 26/49 (53% (38-67%)) of stage I and 59/71 (83% (71-90%)) of stage II cases. Conclusions: MDMs show promise to detect lymphoma. These markers could be evaluated as part of multicancer early detection testing and could also be evaluated as response markers to treatment and subsequent surveillance.[Table: see text]
Prevalence and spectrum analysis of germline <i>DICER1</i> variants of solid tumors: Decoding the mysterious signals of the genome.
Authors: Pibao Li, Tiantian Han, Didi Guo, Ningning Luo, Mengmeng Li, Guanghua Lu, Fanfeng Bu
Journal: Journal of Clinical Oncology (2022)

10578 Background: DICER1 syndrome is a rare genetic condition predisposing to multiple cancer types and causes by germline DICER1 variants. Deleterious mutations identified were mostly located in the RNase III domain. VUSs found in other domains may be also crucial in the inheritance of high-risk neoplasms although there is insufficient evidence. Our study aimed at describing the spectrum of DICER1 variants detected in solid tumors to improve the identification of potentially high-risk DICER1 variants. Methods: Germline mutations including SNV, small INDEL in 448 patients with solid tumors were analyzed by next-generation sequencing (NGS) panel. The pathogenicity of germline mutations was categorized based on American College of Medical Genetics and Genomics (ACMG) guidelines. Results: In total, 3 (0.67%) patients (diagnosed as bladder cancer, schwannoma, and medulloblastoma) were identified harboring truncating pathogenic (P)/likely pathogenic (LP) germline mutations in the RNase III domain. The remaining 445 (99.33%) patients carried 447 uncertain significance (VUS) mutations, of which 416 (92%) were missense mutations lied in different domains and 52% (234/450) located in exon 20-23. The median age was 60 years old with an age range from 0 to 90. The higher frequency cancer type contained lung cancer (35.9%), glioma (10.0%), liver cancer (8.4%). In addition, the two highest frequencies of DICER1 missense variants were c.3334A &gt; G (p. Asn1112Asp, n = 58) and c.3227G &gt; A (p. Ser1076Asn, n = 53), which lied in unknown functional domain of the protein and had been reported in Clinvar. Their clinical significance and pathogenicity remain further study. Conclusions: In our study, DICER1 germline mutations mostly occurred in exon 20-23 and 92% were missense mutations. We reported 3 new cases of tumors associated with DICER1 syndrome, which expanded the DICER1-related tumor spectrum. Understanding the clinical significance of germline DICER1 VUS could improve the identification of potentially high-risk variants. Reclassifying these variants could make them useful for predictive, prognostic, and preventive purposes in clinical practice.
TBIO-05. R-loops in pediatric brain tumors
Authors: Shanzheng Wang, Apurva Gopisetty, Natalie Jäger, Stefan Pfister, Marcel Kool
Journal: Neuro-Oncology (2022)

Abstract R-loops are structures containing DNA-RNA hybrids and displaced single-stranded DNA, which are widely distributed across genomic regions. The generation and removal of R-loops is dynamically regulated by several factors including helicases and topoisomerases. Previously, we have identified high levels of R-loops associated with genomic instability in Embryonal Tumors with Multilayered Rosettes (ETMR) (Lambo et al. 2019), which is associated with a sensitivity to drugs targeting topoisomerases and DNA repair. However, it is unknown whether there are other pediatric cancers with high levels of R-loops, and whether R-loops in these tumors are also associated with genomic instability and sensitivity to specific treatments. Here, we have used real R-loops sequencing data sets, including ETMR DRIP-seq data, and the bioinformatic tool QmRLFS-finder (Wongsurawat et al. 2012), which can predict R-loops forming sequences (RLFSs) based on DNA sequence composition. By performing bioinformatic analyses of DRIP-seq data sets and integrating these with RLFSs from human reference genome simulations, we aim to analyze how reliable the different methods are to measure and predict R-loops and what role they have in cancer genomes. In ETMR, R-loops signals from DRIP-seq data were enriched around transcriptional start sites (TSS), comparable to R-loops distribution and enrichment in other published cell models. However, the overlap with RLFSs was limited, indicating that more validations with real DRIP-seq data from more ETMRs and other pediatric cancers are needed to validate the different methods. Taken together, until now, we developed methods to (semi-)quantify R-loops by combining real sequencing data and computational simulation approaches to investigate R-loops distribution in cancer genomes and to investigate whether R-loops are associated with breakpoints or other genetic aberrations in pediatric cancer entities.
Survival in patients with prostate cancer and history of autoimmune disease.
Authors: Demitrios Dedousis, Annie Zhang, Anastasia Vassiliou, Shufen Cao, Deepthi Yammani, Ravi Kumar Kyasaram, John Shanahan, Melissa C. Keinath, Melinda Laine Hsu, Pingfu Fu, Afshin Dowlati, Jorge A. Garcia
Journal: Journal of Clinical Oncology (2022)

e17001 Background: Prostate cancer is thought of as an immunologically cold tumor, however a small proportion of patients treated with immunotherapy have impressive responses. Studies into the effect of autoimmune disease on risk of prostate cancer have yielded contradictory results and little is known about the survival of patients with concurrent autoimmune disease and prostate cancer. This study compared outcomes in patients with prostate cancer with and without autoimmune disease. Methods: This study was a retrospective analysis of patients from the SEER-Medicare databases from 2007-2014 with prostate cancer. Patients with a history of autoimmune disease were identified using ICD-9 codes. The effects of autoimmune disease on overall survival (OS) and cancer-specific survival (CSS) were estimated using multivariable Cox regression and Gray’s method respectively controlling the effects of age, race and chronic kidney disease (CKD). The cumulative CSS was estimated taking death as a competing risk. Results: The overall prevalence of investigated autoimmune diseases among the 172,061 patients with prostate cancer was 23.74%. The most common autoimmune diseases identified were rheumatoid arthritis (RA) (20.93%), psoriasis (2.43%) and ulcerative colitis (UC) (0.91%). In stage IV prostate cancer, OS (p = 0.018) and CSS (p &lt; 0.001) were significantly higher in patients with autoimmune disease, with a median OS of 55 months compared to 48 months in patients without autoimmune disease. After adjusting for the effects of age, race, and CKD, autoimmune disease was still predictive of higher OS (HR: 1.41, 95% CI: 1.33 – 1.5, p &lt; 0.0001) and CSS (HR: 1.30, 95% CI: 1.21 – 1.39, p &lt; 0.0001). Patients with autoimmune disease and stage II and III prostate cancer had lower OS (p values &lt; 0.0001) compared to patients without autoimmune disease. Conclusions: The study showed higher prevalence of RA, Crohn disease, UC, and systemic lupus erythematosus in patients with prostate cancer compared to cohorts of similar age ranges in the general population. History of autoimmune disease predicted significantly higher OS and CSS in patients with stage IV prostate cancer even when age, race and CKD were controlled for. It is possible that an improvement in OS with a history of autoimmune disease was evident in stage IV but not in stages II and III because anti-tumor autoimmune activity plays a larger role when prostate cancer effects regional lymph nodes or has distant metastases.
Window-of-opportunity study of ONC201 in pediatric patients with diffuse intrinsic pontine glioma (DIPG) and thalamic glioma.
Authors: Yazmin Odia, Carl Johannes Koschmann, Rohinton Tarapore, Jeffrey Allen, Wafik Tharwat Zaky, Matthew David Hall, Doured Daghistani, Ziad Khatib, Dolly Aguilera, Tobey J. MacDonald, Peter de Blank, Susan L. McGovern, Sabine Mueller, Cassie Kline, Nicholas A. Vitanza, Joshua E. Allen, Sharon L. Gardner
Journal: Journal of Clinical Oncology (2022)

TPS2082 Background: H3 K27M-mutant diffuse midline glioma is a universally fatal malignancy primarily affecting children and young adults; while radiotherapy (RT) provides transient benefit, no effective systemic therapy is currently available. ONC201, a first-in-class imipridone, is an oral, blood-brain barrier penetrating, selective small molecule antagonist of dopamine receptor D2/3 and agonist of the mitochondrial protease ClpP. Previously, ONC201 monotherapy demonstrated durable objective responses in adults with recurrent H3 K27M-mutant glioma. This phase 1 trial was designed to evaluate ONC201±RT in pediatric patients with H3 K27M-mutant midline glioma DIPG. Methods: This multicenter, open-label, dose escalation and expansion phase 1 study of ONC201 is comprised of eight arms that will evaluate the recommended phase 2 dose (RP2D) of ONC201, biomarkers, and pharmacokinetics (PK) of ONC201±RT in various treatment settings. Arm G previously defined the RP2D for ONC201 administered twice weekly on consecutive days in patients with H3 K27M-mutant glioma who had completed radiotherapy. Arm H, for which enrollment is ongoing, will estimate the influence of tumor location and blood-brain barrier integrity on PK and intratumoral ONC201 exposure in biopsy-eligible pediatric tumors (DIPG or contrast-enhancing thalamic glioma). Patients eligible for Arm H will be aged 2-≤19 years, ≥2 weeks from last RT administration, and have a Karnofsky/Lansky performance score ≥50; prior confirmation of H3 K27M mutation is not required. In Arm H, single-agent ONC201 administration will occur on two consecutive days each week during each 21-day cycle at the RP2D defined in Arm G. Evidence of disease progression is not required; as such, ONC201 may be administered in the maintenance setting or for recurrent disease. Arm H has a planned enrollment of 27 patients. Each patient will undergo biopsy at a single prespecified biopsy window, which will be assigned at enrollment (Table); plasma for PK analysis will be collected from all patients at all time points shown in the Table, with additional collection pre-dose and 0.5 h post first dose. Clinical trial information: NCT03416530. [Table: see text]
Association between remotely-monitored activity, patient-reported outcomes, and physical function in patients with advanced pancreatic cancer.
Authors: Gillian Gresham, Eileen Liu, Marcio A. Diniz, Katherine Barnhill, Nima Nikravesh, Amelia Welborn, Celina Shirazipour, Arash Asher, Arsen Osipov, Andrew Eugene Hendifar
Journal: Journal of Clinical Oncology (2022)

1572 Background: Patients with pancreatic ductal adenocarcinoma (PDAC) experience significant functional decline over the course of their treatment, which can negatively impact their quality of life (QOL) and clinical outcomes. There are currently no standardized methods to monitor physical function (PF) in PDAC patients outside the clinic setting. The use of wearable technology to obtain continuous and objective activity data combined with routine collection of patient-reported outcomes (PROs) provides an opportunity to monitor PF and intervene in a timely matter. Methods: We conducted a single-site, single-arm prospective study in advanced stage 3 and 4 PDAC patients between 2019 and 2/2022. Patients used a wrist-worn wearable activity monitor (Fitbit) continuously for 8 weeks and completed NIH PROMIS surveys (PF, pain, fatigue, sleep disturbance, and emotional distress) at baseline, week 4 and week 8. ECOG performance status (PS), hand grip strength, and timed 15-foot walk test were also assessed at each timepoint. Pearson correlation coefficients were calculated for activity data (step counts, distance, stairs, time spent sedentary and in light, moderate, or vigorous activity, sleep), PROs, and functional outcomes. Multivariable regression models, adjusted for age, sex, and cancer stage, were fit to evaluate associations between activity metrics, PROs, and functional outcomes. Multivariable cox proportional hazard models were fit to evaluate the impact of activity levels on survival. Results: A total of 40 patients consented onto study: 50% female, median age: 67 years (range 47-85), 92% ECOG 1. Baseline activity data are summarized in Table. Statistically significant correlations between step counts and PF T-scores (coeff: 0.6, p = 0.001) and lower pain scores (coeff: -0.53, p = 0.002) were observed. Increased stairs count and time spent in moderate and high physical activity were also positively correlated with increased PF (p&lt;0.001). No statistically significant correlations were observed between hand grip strength, activity metrics or PROs. Fewer average step counts and worse PF scores were significantly associated with poor survival with hazard ratios (HR) of 1.44 per 1000 steps (95% CI 1.06, 1.97, p = 0.02) and 1.69 (95% CI 1.1-2.56, p = 0.017), respectively, after adjusting for age, sex, stage, and ECOG PS. Conclusions: Findings from this research suggest that the use of wearable technology for remote monitoring of daily activity is feasible and may be used to supplement functional assessment and predict outcomes in PDAC patients. Larger trials are needed to validate findings. [Table: see text]
The anatomical location of lymphadenopathies at imaging predicts the risk of lymph node invasion at final pathology in patients with renal cell carcinoma
Authors: G. Rosiello, G. Fallara, G. Basile, D. Cignoli, F. De Cobelli, G. Brambilla, L. Nocera, F. Belladelli, G. Colandrea, D. Canibus, C. Re, G. Musso, F. Cei, C. Giancristofaro, A. Briganti, R. Bertini, A. Necchi, D. Raggi, A. Mottrie, P.I. Karakiewicz, F. Montorsi, A. Salonia, A. Larcher, U. Capitanio
Journal: European Urology (2022)
Inter-reader reliability of immune-specific response criteria (irRECIST &amp; iRECIST).
Authors: Kathleen Ruchalski, Hyun J. Kim, Rohit Dewan, Michael Douek, Victor Sai, Bianca Villegas, Koon-Pong Wong, Aaron E. Lisberg, Jonathan W. Goldman, Jonathan Goldin, Edward B. Garon, Denise R. Aberle
Journal: Journal of Clinical Oncology (2022)

e21108 Background: RECIST 1.1 can underestimate treatment benefits of immunotherapy, with irRECIST and iRECIST accounting for atypical responses. Inter-reader discordances are known to occur in a dual reader paradigm. Our objective is to compare inter-reader reliability between RECIST 1.1, irRECIST, and iRECIST. Methods: This is a retrospective analysis of advanced NSCLC patients treated with pembrolizumab at our institution as part of the KEYNOTE-001 study. All trial imaging was interpreted by two radiologists. RECIST 1.1, irRECIST, and iRECIST categorical responses and agreement for progressive disease (PD) was compared by kappa statistic. Time to progression (TTP) or time to censor was compared between readers by paired t test. Relationship to disease progression and overall survival (OS) was assessed by log rank. Results: Of 98 patients, 77 had baseline and subsequent imaging available for 5.8 mean timepoints with 42.9 weeks of follow up. From this group, 45 patients had imaging beyond iUPD for confirmation and were analyzed. PD occurred by reader 1, reader 2 in 34, 33 patients by RECIST 1.1 (k = 0.591, CI = 0.320-0.863), 31, 29 patients by irRECIST (k = 0.501, CI = 0.234-0.768), and 27, 22 patients by iRECIST iCPD (confirmed-PD) (k = 0.690, CI = 0.485-0.896). There was no significant difference in reader agreement by RECIST 1.1, irRECIST, iRECIST (p = 0.38, 0.60, 0.26). There was a significant difference in time to progression between RECIST 1.1, irRECIST and iRECIST, with median PFS 3.4 months (2.6-4.6), 4.7 (3.5-6.8) and 8.7 (6.9-14.5) (p &lt; 0.0001). PD by any criteria was not significantly correlated with OS. Conclusions: PD confirmation by iRECIST resulted in substantial reader agreement compared to moderate reader agreement by RECIST 1.1 and irRECIST. There were significant differences in TTP between the criteria, with iRECIST having the longest TTP. PD by each criteria did not correlate with a significant difference in OS.[Table: see text]